Is CFHR2 p.Glu199Val (c.596A>T) pathogenic?

CFHR2 p.Glu199Val (c.596A>T) is classified Uncertain significance in CFHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely benign (0.1503); Very rare (popmax 0.00254%, nfe).

How common is CFHR2 p.Glu199Val (c.596A>T) in the general population?

CFHR2 p.Glu199Val (c.596A>T) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about CFHR2 p.Glu199Val (c.596A>T)?

AlphaMissense predicts likely benign (score 0.1503) — an in-silico prediction, not a clinical call.

CFHR2 p.Glu199Val

c.596A>T · rs1362108171 · VCV2396924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1503	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -10.33	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 1.8
Regional constraint	o/e 1.00	unconstrained · MANE · 15 kb · p 0.97 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,526 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00192% 31/1,613,362 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,318
African / African-American	0.00134%	74,900

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CFHR2
Protein: p.Glu199Val
Coding: c.596A>T
MANE Select: NM_005666
dbSNP: rs1362108171
Type: single nucleotide variant
Location: chr1:196958056 (GRCh38)
Gene constraint: LOEUF 1.498 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 4 PDB
Residue 199: a disulfide bond; an α-helix; the sushi 3 domain

Full CFHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR2 p.Glu199Ter Benign/Likely benign ★★ same residue
CFHR2 p.Val16Ala Uncertain significance ★★ ⚠ same type
CFHR2 c.430+141T>A Benign ★★ same type
CFHR2 c.430+20C>T Benign ★★ same type
CFHR2 c.430+7G>A Benign/Likely benign ★★ same type
CFHR2 c.431-48C>A Benign ★★ same type
CFHR2 c.431-65C>T Benign ★★ same type
CFHR2 c.58+129C>G Benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfhr2-p-glu199val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown